Pharmaceutical composition based on 11-halogen substituted steroids

ABSTRACT

Pharmaceutical composition containing as active ingredient an 11-halogen substituted steroid of the formula   WHEREIN R is hydrogen, aliphatic acyl of up to 15 carbon atoms or aliphatic acyl having up to a total of 15 carbon atoms and being substituted with chlorine, or a carboxylic acid group, a nitryl group or a sulphate group and wherein X and Y are halogen, the molecular weight of Y being at least equal to that of X. The compositions of the invention are useful particularly as anti-inflammatory agents. The invention also embraces a method of treating patients suffering from inflammatory conditions with the defined compositions.

United States Patent Laurent et a1.

July 3, 1973 PHARMACEUTICAL COMPOSITION BASED ON ll-IIALOGEN SUBSTITUTEDSTEROIDS Inventors: Henry Laurent; Ulrich Kerb;

Karl-Heinz Kolb; Rudolf Wlechert; Erich Gerhards, all of Berlin, GermanySchering Aktiengesellschaft, Berlin, Germany Filed: Aug. 20, 1971 Appl.No.: 173,638

Related U.S. Application Data Division of Ser. No. 753,034, Aug. 15,1968, Pat. No. 3,609,171.

Assignee:

Foreign Application Priority Data Aug. 16, 1967 Germany P 16 43 036.7

ms. Cl. 424/242 Int. Cl A6lk 17/00 Field of Search 424/242; 260/397.45

References Cited UNITED STATES PATENTS 9/1971 Laurent et a1. 260/397.453/1970 Basco 260/397.45 2/1969 Kieslich et a1. 424/243 l/l969 Shapiro eta1... 424/243 l/l968 Shapiro et a1 260/397.45

Primary Examiner-Shep K. Rose Attorney-Michael S. Striker ABSTRACT-Pharmaceutical composition containing as active ingredient an 1l-halog'en substituted steroid of the formula CHgOR wherein R ishydrogen, aliphatic acyl of up to 15 carbon atoms or aliphatic acylhaving up to a total of 15 The compositions of the inventionparticularly as anti-inflammatory agents,

are useful The invention also embraces a method of treating patientssuffering from inflammatory conditions with the defined compositions.

.31 Claims, No Drawings PHARMACEUTICAL COMPOSITION BASED ON I l-IIALOGENSUBSTITUTED STEROIDS CROSS-REFERENCES TO RELATED APPLICATIONS Thisapplication is a division of application Ser. No. 753,034, filed Aug.15, 1968 now US. Pat. No. 3,609,171.

BACKGROUND OF THE INVENTION Steroids are known which have ananti-inflammatory reducing effect. For instance, 6a-fluoro-l 1,8,21-hydrogen-l a-methyl-l ,4-pregnadiene-3 ,20-clione has been used for thispurpose. However, it appeared desirable to improve the prior artcompounds as to the onset of their action and also as to the timeinterval existing between onset and maximum effect.

There was furthermore a desire to increase the effectiveness of thedrugs and to eliminate or further reduce undesirable side effects.

SUMMARY OF THE INVENTION It is, therefore, a specific object of thepresent invention to provide an anti-inflammatory composition whichrapidly becomes effective after its administration.

The above and other objects as will appear from the specification thatfollows are accomplished by a pharmaceutical composition containing asactive ingredient an ll-halogen substituted steroid of the formula CHrORwherein R is hydrogen, aliphatic acyl of up to carbon atoms or aliphaticacyl having up to a total of 15 carbon atoms and being substituted withchlorine, or a carboxylic acid group, a nitryl group or a sulphate groupand wherein X and Y are halogen, the molecular weight of Y being atleast equal to that of X.

The invention also embraces a method of treating patients suffering frominflammatory conditions with the defined compositions.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 7 With reference to the generalformula set forth in the above summary, it will be understood that R maycomprise physiologically acceptable acid residues as they are used inconventional process in steroid chemistry for esterification of freehydroxyl groups. Preferred are esters having up to 15 carbon atoms,particularly of the lower and intermediate aliphatic carboxylic acids.The acids can also be unsaturated, branched, polycarboxylic orconventionally substituted, for instance by hydroxy or amino groups orhalogen atoms themselves. Suitable cycloaliphatic, aromatic, mixedaromaticaliphatic or heterocyclic acids, all of which may also besubstituted in a suitable manner. Examples of such acids are thefollowing: formic acid, acetic acid, propionic acid, butyric acid,valeric acid, caproic acid, enanthic acid, undecylic acid,trimethylacetic acid, diethyla- CHzOR wherein R is hydrogen or acyl.

These starting products can be obtained by dehydrating the correspondingll-hydroxy compounds. The dehydration can be effected, for instance, byreacting the l1-hydroxy-2l-acyloxy-steroids with methanesulfochloride inpyridine and dimethylformamide.

For instance, 6a-fluoro-2l-hydroxy-I6a-methyl---l,4,9(1l)-pregnatriene3,20-dione can be obtained in a smooth reactionby saponifying the corresponding 2 l -ester.

The addition of the halogen to the A -double bond can be effected in anumber of ways. For instance, halogens such as chlorine or bromine orintercompounds of different halogens such as chlormonofluoride orbrommonochloride or halogens derived from polyhalides such as potassiumtriiodide or iodobenzyldichloride, may be substituted directly at thedouble bond by an addition reaction. The halogen substitution willproceed with greatest ease if the A -steroids are simultaneously reactedwith a positive and a negative halogen. Reagents containing a positivehalogen are, for instance, halogenosuccinimide, halogenoacetamide or thehalogens proper. Reagents for supplying the negative halogen are, forinstance, the hydrogen halides and alkali metal halides. Thesubstitution of the halogen at the A double bond of the steroid alwaysproceeds in a manner where the positively charged halogen attaches tothe 9-position and the negatively charged halogen attaches to the ll-position of the molecule. The molecule weight of the halogen in the 9-position therefore can never be smaller than that of the halogen in thel l-position. The halogen addition to the A -double bond is preferablycarried out at temperatures between -C and +50C.

The free hydroxyl group or ester group in the 21- position cansubsequently be esterified or saponified in conventional manner. It isadvisable, however, to use mild conditions in order to obtain a goodyield.

The new compounds have an excellent antiinflammatory action, asdetermined in vasoconstriction tests carried out with male test subjectsafter local application. This is further illustrated by the data listedin Table 1 below, where compounds II to IX are compared with the priorart Compound I, 6a-fluoro-l 13,21- dihydroxyl Ga-methyll,4-pregnadiene-3 ,20-dione.

The vasoconstriction test to determine the clinical experimentalsuperiority of the compounds of the invention was carried out asfollows:

The stratum corneum on the backs of male test subjects of the ages 18 to38 was abraded with a Tesa film of 2 cm width by means of 20 scratchesapplied above each other so as to cause a marked hyperernia. 4 cm largeareas were then set apart in the exposed skin portion and 50 mg of awater/oil ointment base were applied to those areas upon simultaneousapplication of pressure. The base in each instance contained 0.01percent, 0.001 percent and 0.0001 percent, respectively, of the testcompound. The back of the subject was then photographed with a Kodakcolor film at predetermined intervals. The color of the individual skinareas appearing on the Kodak color film was then converted into lightintensity values for determining the hyperemia and vasoconstriction. Theportions projected by the color film through an apertured disk onto aninterference filter could then be distinguished by their lightintensity. A secondary electron multiplier of the FS 9 A type was usedas light intensity indicator and the color value was measured by theanode current of the secondary multiplier. The color value of theuntreated and the treated abraded skin was determined and compared withthe color value of normal skin, since vasoconstriction can be consideredas the representative symptom of an anti-inflammatory action and can beused to appraise the inception, intensity and duration of the action.The color value of the normal skin in these tests was set at 100 and thecolor value of untreated abraded skin was set at 0. There could thus beevaluated low, intermediate and high vasoconstriction by ascertainingthe values between and 100.

TABLE 1 Time after which observation took place (in hrs.)

Test Dose No. Compound l 2 3 4 5 6 7 l 6a-fluoro-11/3,21- 0.01 0 25 4050 100 dihydroxy-l6a- 0.001 0 20 44 100 methyl-1A 0.0001 0 15 25 50 t{06 pregnadiene- 3,20-dione n 6a-fluoro-9,l 1B- dichloro-21-acetoxy-lfia- 0.01 5 30 75 95 100 methyl-1,4- 0.0001 0 15 30 60 85 100pregnadiene- 3,20-dione 111 6a, llB-difluoro- 9-ch1oro-21- 0.01 15 35100 acetoxy-l6a- 0.001 15 40 75 100 methyl-1,4- 0.0001 0 30 60 90 100pregnadiene- I 3,20-dione IV 601.1 1B-difluoro- 9-chloro-21- trimethyl-0.01 25 55 100 acetoxy-16a- 0.001 10 50 75 100 methyl-1,4- 0.0001 10 4060 100 pregnadiene- 3,20-dione v 6a.] lfl-dlfluoro- 9-chloro-21- 0.01 1545 95 100 butyryloxy- 0.001 15 50 75 100 16a-methyl-1,4- 0.0001 0 30 55100 pregnadiene- 3,20-dione VI ,6u-flu0r09,ll

dicl'lloro ltrimethyl- 0.01 10-55 85 100 acetoxy-16a- 0.0001 10 40 75 90100 methyl-1 ,4- pregnadiene- 3,20-dione vn 6(x-flu0r0-9.l 1B dichloro-Z1 butyryloxyl6a-methyl-1,4-

pregnadiene- 3,20-dione fizz-fluoro- 9,11fl-dichloro 0.01

21-valeryloxy- 0.001 16a-methyl-1,4- 0.0001

pregnadiene- 3,20-dione The above tests of Table 1 clearly demonstratethat apart from an earlier inception of the action, the desired maximumdegree of activity is reached faster with the compounds of the inventionthan with the comparison compound. The intensity of action of the newcompounds is also greater throughout the time tested than with the knownproduct. In addition, there is a more desirable absence of side effectswith the compounds of the invention. For instance, the carbohydratemetabolism is effected either not at all or only to a minor extent. Thegluconeogenetic action is also substantially reduced as appears, forinstance, from the fact that the blood sugar concentration is notincreased and that the liver glycogen starts increasing only at anextremely high dose. There is also only a minor effect on the liverenzyme, tryptophane pyroolase and the transminases GOT and GPT.Significantly minor changes in sodium, potassium and phosphateelimination also are observed under the action of the compounds of theinvention.

The compounds of the invention are valuable in combination with theconventional carriers used in Galenical pharmacy for use in thetreatment of a number of diseases, such as:

[a] by local administration: contact dermatitis, varied eczemas,neurodermatitis, erythrodermia, first degree burns, pruritus vulvae etani, rosacea erythematodes cutaneus, psoriasis, lichen rubber planus andverrucosus;

[b] by oral administration: acute and chronic polyarthritis,neurodermatitis, bronchial asthma, hay fever,

etc.

The following examples will further illustrate the invention without inany way limiting the scope thereof.

EXAMPLE 1 18 ml anhydrous fluoric acid were reacted with 25 m1tetrahydrofuran and 35 ml methylenechloride at -75C. 8.70 g6oz-fluoro-21-acetoxy-l6a-methyl- 1,4,9( 1 1)-pregnatriene-3,20-dione(melting point 160-l62C) and 4.6 g N-bromosuccinimide were dissolved inthis mixture. The solution was stirred for 3.5 hours at 50C and thenpoured into a solution of g sodium bicarbonate in 3.5 liters water. Theresulting solution was then extracted with methylene chloride and theorganic phase was washed with water and dried and the solvent evaporatedin vacuum. There were obtained from acetone hexane, 6.39 g 601,1lfl-difluoro-Q- bromo-21-acetoxy-16a-methyl-1,4-pregnadiene-3 ,20-

EXAMPLE 2 42 ml anhydrous fluoric acid, 57 ml tetrahydrofuran and 80 mlmethylenechloride were added together at 75C. 20 g6a-fluoro-21acetoxy-16a-methyll,4,9(l 1 )-pregnatriene-3,20-dione and N-chlorosuccinimide were dissolved in this mixture, and after stirring thesolution for 5 hours at 60C, additional g N-chlorosuccinimide were addedand the reaction mixture was permitted to stand for 16 hours at 0C. Themixture was then poured into a solution of 270 g sodium bicarbonate in 3liters water and was extracted with methylenechloride. The organic phasewas washed with a sodiumhydrogensulfide-sodiumbicarbonate solution andwater. After drying, the solvent was evaporated in vacuum. There wereobtained from acetone/hexane 12.4 g 6a, 1B-difluoro-9-ch1oro-21-acetoxy-l6a-methyl-1,4-pregnadiene-3,20-dione with a melting point of249.5250C. UV: e 15,900.

EXAMPLE 3 A solution of 1.0 g 601,11B-difluoro-9-bromo-21-acetoxy-16a-methyl-l ,4-pregnadiene-3 ,20-dione in 3.0 mlmethylenechloride was reacted at 10C with 6.2 ml of a 0.2 Nsodiummethylate solution in methanol. The reaction was subjected tostirring for 45 minutes in a nitrogen atmosphere at -10C, neutralizedwith acetic acid and extracted with methylenechloride. The organic phasewas washed with sodium bicarbonate and water, dried and concentrated invacuum. The residue was recrystallized from acetone/hexane. There wereobtained 774 mg 611,11B-difluoro-9-bromo-21-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione with a melting pointbetween 206 and 206.5C. UV: 6 14,900.

EXAMPLE 4 1.0 g 601,1lB-difluoro-9-chloro-21acetoxy-16amethyl-l,4-pregnadiene-3,20-dione wassaponified with sodium methylate, following the conditions given inExample 3. There were obtained 770 mg 611,113- difluoro-9-chloro-2 1-hydroxy-1 6a-methyl-1 ,4-pregnadiene-3,20-dione, melting point 211.5 to214C (acetone/hexane). UV: e 16,500.

EXAMPLE 5 A solution of 2.75 g6a,11B-difluoro-9-bromo-2lhydroxy-16a-methyl-1,4-pregnadiene-3,20-dionein 1 1 ml pyridine and 5.5 ml butyric acid anhydride was permitted tostand for 16 hours at room temperature. The precipitated crystallinesubstance was isolated after addition of water and was twicerecrystallized from acetone. There were obtained 2.45 g6a,11B-difluoro-9- bromo-2 1 butyryloxy- 1 6a-methyl-l ,4-pregnadiene-3,20-dione with a melting point between 164.5 and 16- 5.5C. UV: e15,000.

EXAMPLE 6 3.95 g 601,1 lB-difluoro-9-chloro-2l-hydroxy-l 6amethyl-l,4-pregnadiene-3,20-dione were reacted in the manner stated in Example5. There were obtained 3.16 g 6a,] 1B-dif1uoro-9-chloro-21butyryloxy-lGot-methyl- 1,4-pregnadiene-3,20-dione with a melting point between 183and 184C (acetone/hexane). UV: e 16,600.

EXAMPLE 7 A solution of 2.75 g 6a,] lB-difluoro-9-bromo-21- hydroxyl6a-methyl-l ,4-pregnadiene-3,20-dione in 40 ml methylenechloride wasreacted with 5.5 ml trimethylacetic acid anhydride and 14 ml ofa 20percent aque- EXAMPLE 8 3.73 g 601,11B-difluoro-9-chloro-2l-hydroxy16amethyl-1,4-pregnadiene-3,20-dione were reacted with trimethylaceticacid anhydride in the manner described in Example 7. There were obtained3.04 g 601,113- dif1uoro-9-chloro-2 l trimethylacetoxyl 6a-methyl-1,4-pregnadiene-3,20-dione with a melting point between 196 and 198C(acetone/hexane). UV: 6 16,500.

EXAMPLE 9 A solution of 10.0 g6a-fluoro-21-acetoxy-16amethyl-1,4,9(11)-pregnatriene-3,20-dione in 300ml acetic acid was reacted with 50.0 lithium chloride and a solution of2.3 g chlorine in 200 m1 acetic acid and was subjected to stirring for2.5 hours at room temperature. The solution was then poured into water,the precipitated product was removed by suction, washed with water anddried in vacuum. The crude product was subjected to chromatographythrough silica gel. After recrystallization from acetone/hexane, therewere obtained 2.23 g 6a-fluoro-9,1lB-dichloro-Zl-acetoxyl6a-methyl-l,"4-pregnadiene-3,20-dione with a melting point between 239 and 240C.UV: e 16,200.

EXAMPLE l0 6 ml anhydrous fluoric acid were reacted at C with 9 mltetrahydrofuran and 12 ml methylene chloride. 3.0 g6a-fluoro-21-hydroxy-16a-methyl- 1,4,9(l 1)-pregnatriene-3,20-dione(melting point 172-l73C) and 1.5 g N-bromosuccinimide were dissolved inthis mixture. It was then subjected to stirring for 4 hours at 5C andpoured into a solution of 40 g sodium bicarbonate in 1.2 liters water,followed by drying and evaporation in vacuum. After recrystallizationfrom acetone/hexane, there were obtained 1.57 g 6010:,- 1lB-difluoro-9-bromo-2l hydroxy-l 6a-methyl-l ,4- pregnadiene-3,20-dionewith a melting point between 205 and 206C. UV: e 14,800.

EXAMPLE 1 1 A solution of 1.68 g 6a-fluoro-21-acetoxy-16amethyl-1,4,9( 11 )-pregnatriene in ml acetic acid was reacted with 8.5 g lithiumchloride, 1.68 g N- bromoacetamide and 3.4 ml HCl-saturated dioxane. Themixture was subjected to stirring at room temperature for 1 hour, thenpoured into water, whereupon the precipitated product was removed bysuction, washed with water and dried in vacuum. After recrystallization,there were obtained 1.29 g 6a-fluoro-l 1B-chloro-9--pregn'adiene-3,20-dione methyl-1,4,9,(1 1 )-pregnatriene3,20-dione 7bromo-2 1acetoxy-l6a-methyl-1,4-pregnadiene-3 ,20- dione with a meltingpoint of 186.5 to 187.5C. UV: e 14,300.

EXAMPLE 12 6.7 g 6a-fluoro-11B-chloro-9-bromo-21acetoxy-16a-methyl-1,3-pregnadiene-3,20-dione were saponified with sodiummethylate in the manner described in Example 3. The yield was 4.8 g6a-f1uoro-11B-chloro- 9-bromo-21-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione with a melting point between 162 and 163- C. UV: e 14,400.

EXAMPLE 13 A solution of 250 mg 6afluoro-1 1B-chloro-9-bromo-21-hydroxy-16a-methyl-l ,4-pregnadiene-3 ,20-dione in 1.25 mldimethylformamide was reacted with 0.5 ml chloroacetylchloride undercooling with ice. The mixture was stirred at room temperature for 45minutes and subsequently poured into water. The precipitate was removedby filtration, washed, dried and recrystallized from acetone/hexane.Yield: 180 mg 6a-fluoro- 1 1B-chloro-9-bromo-21chloroacetoxy-l6a-methyl-1,4-pregnadiene-3,20-dione with a melting point between 197.5 and 198C.UV: e 14,600.

EXAMPLE 14 1.0 g6a-fluoro-9,11B-dichloro-21-acetoxy-16ozmethyl-1,4-pregnadiene-3,20-dionewere saponified in the manner described in Example 3. There wereobtained 780 mg 6a-fluoro-9,l1B-dichloro-21-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione with a melting point between 213and 218C (acetone/hexane). UV: e 17,000.

EXAMPLE 15 7.0 ml acetic acid anhydride were reacted with 4.5 ml conc.nitric acid (D=1.50) at C. To this mixture was added, under stirring, asolution of 700 mg 6afluoro-9 ,1 1B-dichloro-21 hydroxy-l 6a-methyl-1,4- pregnadiene-3,20-dione in 30 ml chloroform. The mixture wassubjected to stirring at 10C for 30 minutes,

- poured into ice water and extracted with methylenechloride. Theorganic phase was washed with a sodiumbicarbonate solution and water,dried, and concentrated in vacuum. The residue was recrystallized fromacetone/hexane. There was obtained 407 mg 6afluoro-9,1 lB-dichloro-Z1-nitryloxy-16a-methyl-l,4-

with a melting point 198200C. UV: e 16,700.

, 7 EXAMPLE 16 A solution of 500 mg 6a-fluoro-21-hexanoyloxy-16a-(melting point 1 19.5-120C) in 25 ml conc. acetic acid was reacted with2.5 g lithium chloride, 500 mg N- bromosuccinimide and 1.0 mlHCl-saturated dioxane. The mixture was subjected to stirring at roomtemperature for 45 minutes and then poured into water. The precipitatedproduct was removed by suction, washed with water and dried in vacuum.After recrystallization from methanol there were obtained 444 mg6a-fluoro- 1 1B-chloro-9-bromo-21hexanoyloxy-l6a-methyl-1,4-pregnadiene-3,20-dione with a melting point between 113 and 115C. UV: e15,200.

EXAMPLE 17 3.0 g methyl-l,4-pregnadiene-3,20-dione were reacted withtrimethylacetic acid anhydride in the manner described in Example 7. Thecrude product was then purified by' chromatography through silica gel.By elution with 9.5-12 percent acetone/pentane there were obtained 980mg 6a-fluoro-9a,1 1B-dichloro-21- trimethylacetoxyl 6a-methyl- 1,4-pregnadiene-3 ,20- dione with a melting point 189190C(acetone/hexane). UV: 6 14,700.

EXAMPLE 18 8.5 ml anhydrous fluoric acid, 11.5 ml tetrahydrofuran and 16ml methylene chloride were added together at C. 4.0 g6a-fluoro-21-hexanoyloxy-16amethyl-l,4,9(11)-pregnatriene-3,20-dione and8.0 g N chlorosuccinimide were dissolved in this mixture and the productwas then stirred for 3 hours at 50C and thereafter was permitted tostand for another 16 hours at 0C and was then finally poured into asolution of 45 g sodium bicarbonate in 1.5 liters water, was dried withsodium sulfate and subjected to evaporation of the solvent in vacuum.The residue was recrystallized from acetone/hexane. There were obtained3.10 g 601,113- difluoro-9oz-chloro-2l-hexanoyloxy-16a-mcthyl-1,4-pregnadiene-3,20-dione with a melting point between 121-122C(acetone/hexane). UV: e 15,500.

EXAMPLE 19 A solution of 3.82 g6a-fluoro-21hexanoyloxy-16amethyl-1,4,9(11)-pregnatriene-3,20-dione in20 ml conc. acetic acid was reacted with 20 g lithium chloride, 3.82 gN-chlorosuccinimide and 3.82 ml HClsaturated dioxane. The solution wasstirred for 1 hour and poured into water, whereupon the precipitatedproduct was removed by suction, washed with water, and dried. The crudeproduct was subjected to chromatography through silica gel. Elution with10.5-1 1.5 percent acetone/pentane yielded 1.61 g 6a-fluoro9a,1 1B-dichloro-21hexanoyloxy-16a-methyl-1,4-pregnadiene-3,20-dione, meltingpoint 124-126.7C (acetone/- hexane). UV: 6 15,600.

EXAMPLE 20 2.0 g 6a-fluoro-9,11B-dichloro-21hydroxy-16amethyl-1,4-pregnadiene-3,20-dione were reactedin the manner described in Example 5. The crude product was subjected tochromatography through silica gel. Elution with 10-16 percentacetone/pentane yielded 1.06 g 6a-fiuoro-9a,l1B-dich1oro-21butyryloxy-l6amethyl-l,4-pregnadiene-3,20-dione with amelting point between 203 and 203.5C (acetone/hexane). UV: 6 16,000.

EXAMPLE 21 A solution of 3.3 g 6a-f1uoro-9,llfi-dichloro-Zlhydroxy-16oz-methyl-1,4-pregnadiene-3 ,20-dione in 13.2ml pyridine and 6.6 ml valeric acid anhydride was stirred at roomtemperature for 16 hours. The pyridine and the excess valeric acidanhydride were subsequently distilled off with steam. The residue fromthe distillation was extracted with methylene chloride. The extract wasthen washed wit sodium bicarbonate and water, dried with sodium sulfate,and concentrated in vacuum. The residue was subjected to chromatography6a-fluoro-9,1 1B-dichloro-21hydroxy-16athrough silica gel. Elution with10-13 percent acetone/pentane yielded 2.2 g 6a-fluoro-9a,1lfi-dichloro-21-valeryloxy-16a-methyl-1,4-pregnadiene-3,20-dione with a melting pointbetween 122 and 123C (acetone/hexane). UV: e 14,800.

EXAMPLE 22 5.0 g 601,1 1B difluoror-9-ch1oro-21-hydroxy 16o!-methyl-1,4-pregnadiene-3,20-dione were reacted with valeric acidanhydride in the manner described in Example 21. The isolated crudeproduct was twice recrystallized from acetone/hexane. There wereobtained 4.40 g601,11B-dif1uoro-9a-chloro-21-valeryloxy-16amethyl-1,4-pregnadiene-3,20-dionewith a melting point between 142 and 143C. UV: e 15,800.

EXAMPLE 23 A solution of 100 mg 6a-fluoro-9a,1 l B-dich1oro-21---hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione in 2.0 ml pyridine wasreacted with 400 mg succinic acid anhydride, subjected to stirring for24 hours at room temperature and then poured into water and extractedwith ether. The ether phase was washed with 4 N sulfuric acid and water,dried, and concentrated in vacuum. The residue was subjected totrituration with hexane, followed by isolation of the crystallinecompound. There were obtained 73 mg 6a-fluoro-9a,11B- dich1oro-3,20-dioxo-16a-methyl-1 ,4 -pregnadiene- 21-yl-hydrogen succinate with amelting point of 176- 179C. UV: e 15,900.

EXAMPLE 24 EXAMPLE 25 0.45 ml of sulfuric trioxide was added dropwise atC to 7.5 ml anhydrous pyridine. The mixture was reacted at 0C with 3.7 g611,1IB-difluoro-Q-chloro-Zlhydroxy-16a-methyl-1,4-pregnadiene-3,20-dione and subsequently stirred for 1 hour at C. Thereaction solution was diluted with 80 ml water, was brought up to apl-lof 8.6 with sodium hydroxide and was extracted repeatedly with methylenechloride. The aqueous phase was concentrated in vacuum at 40C and theresidue was digested with methanol. Theundissolved material was removedby filtration. The methanol was then distilled off in vacuum and theresidue was dried over phosphorus pentoxide. There were obtained 4.6 g

methyl-1,4-pregnadiene-21-yl)-su1fate, which dissociated above 160C uponsintering. UV: e 15,700.

EXAMPLE 26 1.0 g 6a-fluoro-9,1 IB-dichloro-Z 1 -hydroxy- 1 611-methyl-1,4-pregnadiene-3,20-dione were reacted in the manner describedin Example 25 with sulfur trioxidelpyridine and subsequently with sodiumhydroxide. There were obtained 1.2 g sodium-(6a-fluoro-9,11B- dichloro-3,20-dioxo-16a-methyl-1,4-pregnadiene-21- yl)-sulfate, whichdisintegrated above 150C upon sintering. UV: e 15,900.

The following examples illustrate pharmaceutical compositionsincorporating effective amounts of the compounds of the invention. Thepharmaceutical compositions may be in the form of ointments, tablets,eyedrops, nose-drops or ear-drops, as desired. They can also be preparedin the form of solutions suited for injection. Preferably, thepharmaceutical compositions should contain the following amounts of thecompounds of the invention:

1. ointments: 0.0001 up to 0.1 percent active ingredient 2. tablets:0.01 to 50 mg per tablet 3. eye-, noseand ear-drops: 0.01 to 1 percentactive ingredient.

4. solutions for injection: 0.1 to 1 percent active ingredient.

Preferably, the'composition is applied in a dose of about 1 to mg in thecase of an ointment, about 1 to 10 tablets, about 1 to 20 drops, and 0.1to 3 ml solution.

EXAMPLE 27 Composition for an ointment:

0.01 g 601,1 lB-difluoro-9-chloro-21-trimethylacetoxy-l6a-methyl-1,4-pregnadiene- 3,20-dione 5.00 g white waxDAB 6 (Deutsches Arzneibuch 6) 5.00 g wool, fat, anhydrous, DAB 6 20.00g vaseline, white DAB 6 25.00 g Amphocerin K Dehydag 14.97 g paraffinoil, liquid DAB 6 30.00 g water, desalted 0.02 g Crematest Perfume OilN0. 6580 Dragee EXAMPLE 28 Composition for an ointment:

0.01% 604,1 1B-difluoro-9-chloro-2 1 -hydroxy- 16amethyl-1,4-pregnadiene-3,20-dione 0.01% 601,11B-difluoro-9-chloro-2l-butyryloxy-1 6amethyl-1,4-pregnadiene-3,20-dione 2.50% Allercurhexachlorophenate, micronized to a particle sizeof about 8 ;1.(Allercur registered trade mark for1-p-chlorobenzyl-2-pyrrolidy1-methylbenzimidazole) 6.00% Hostaphat KW340 (tert. ester of phosphoric acid and paraffin alcoholtetraglycolether) 0.10% sorbic acid 10.00% neutral oil (Migloyol 812)3.50% stearyl alcohol 1.50% wool fat, anhydrous, DAB 6 75.90% desaltedwater EXAMPLE 29 Composition for a tablet:

0.250 mg 6a-fluoro-9,l lfi-dichloro-Zl-trimethylacetoxy-16a-methy1-l,4-pregnadiene-3 ,20-dione 36.000 mg lactose DAB 6 75,780 mg cornstarchUSP XVI 0.500 mg sodiumlaurylsulfate (Texapon K 1.2)

Dehydag, USP XVI 1.400 mg gelatin, white DAB 6 6.000 mg talcum DAB 60.024 mg Nipagin M" (p-oxybenzoic acid methyl ester) DAB 6, 3.(Deutsches Arzneibuch 6, 3rd Supplement) 0.01 1 mg Nipasol M(p-oxygenzoic acid propyl ester) DAB 6, 3rd Supplement 0.035 mg pigmentPistachio Green Dragoco EXAMPLE 30 Composition for a tablet:

0.025 mg 6a-flu01'0-9,l IB-dichloro-Zl-acetoxy-l6amethyl-l,4-pregnadiene-3,20-dione 36.475 mg lactose DAB 6 75.530 mg cornstarchUSP XVI 0.500 mg sodiumlaurylsulfate (Texapon K 12) Dehydag USP XVI1.400 mg gelatin, white, DAB 6 6.000 mg talcum DAB 6 0.024 mg Nipagin M(p-oxybenzoic acid methyl ester) DAB 6, 3rd Supplement 0.01 1 mg NipasolM (p-oxybenzoic acid propyl ester) DAB 6, 3rd Supplement 0035 mg pigmentPistachio Green Dragoco EXAMPLE 31 Composition for a tablet:

0.050 mg601,1lB-difluoro-9-chloro-2l-acetoxy-l6amethyl-1,4-pregnadiene-3,20-dione76.515 mg cornstarch USP XVI 36.000 mg lactose, DAB 6 6.000 mg talcum,DAB 6 1.400 mg gelatin, white DAB 6 0.024 mg Nipagin M (p-oxybenzoicacid methyl ester) DAB 6, 3rd Supplement 0.01 1 mg Nipasol M(p-oxybenzoic acid propyl ester) DAB, 3rd Supplement As is customary,the tablets were produced on a tablet press. I

EXAMPLE 32' Preparation. of Ear-Drops:

100 mg 6a,l 1B-difluoro-9-chloro-2 1-hexanoyloxyl6a-methyl-l,4-pregnadiene-3,20-dione were dissolved in 100ml 1,2-propylene glycol/ethyl alcohol (9:1

EXAMPLE 33 Preparation of Eye-Drops (Oily):

100 mg6a-fluoro-9,lIB-dischloro-Zl-valeryloxyl6a-methyl-l,4-pregnadiene-3,20-dionewere dissolved in 100 ml castor oil. After addition of 200 mgChloramphenicol (or another bacteriostatic agent) thereto, the solutionwas sterilized by filtration and aseptically drawn off.

EXAMPLE 34 Preparation of Eye-Drops (Aqueous):

100 mg sodium-( 601,1 1B-difluoro-9-chloro-3,20- dioxo- 1 6a-methyl-l,4-pregnadiene-21-yl)-su1fate were dissolved in 100 ml distilled waterand after addition thereto of g sulfaethylthiodiazole the solution wassterilized by filtration and drawn off aseptically.

EXAMPLE 35 Preparation of Nose-Drops (Aqueous):

dioxo-l6a)-methyl-1,4-pregnadiene-2l-yl)-sulfate and 2 g Chloramphenicolwere dissolved in 100 ml distilled water.

EXAMPLE 36 Preparation of a Solution for Injection Purposes:

50 mg 601,11B-difluoro-9-chloro-2l-valeryloxy-16w methyl-l,4-pregnadiene-3,20-dione were dissolved in 10 ml sesame oil and thesolution was poured into 1 ml ampoules and sterilized in the customarymanner.

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can by applying current knowledgereadily adapt it for various applications without omitting featuresthat, from the standpoint of prior art, fairly constitute essentialcharacteristics of the generic or specific aspects of this inventionand, therefore, such adaptations should and are intended to becomprehended within the meaning and range of equivalence of thefollowing claims.

What is claimed as new and desired to be protected by Letters Patent isset forth in the appended claims:

1. A pharmaceutical composition containing a pharmaceutically acceptablecarrier and as active ingredient an ll-halogen substituted steroid ofthe formula CEHzOR (5:0

WU- w wherein R is hydrogen, aliphatic acyl of up to 15 carbon atoms oraliphatic acyl having up to a total of 15 carbon atoms and beingsubstituted with chlorine, or a carboxylic acid group, a nitryl group ora sulphate group and wherein X and Y are halogen, the molecular weightof Y being at least equal to that of X.

2. The pharmaceutical composition of claim 1, which is in the form of anointment and contains about 0.0001 to 0.1 percent active ingredient.

3. The pharmaceutical composition of claim I, which is in the form oftablets, each tablet containing about 0.01 to 50 mg active ingredient.

4. The pharmaceutical composition of claim 1, which is in the form ofdrops for eye, nose or ear applications and containing about 0.01 to 1.0percent active ingredient.

5. The pharmaceutical composition of claim 1, which is in the form of asolution for injection containing about 0.1 to 10 percent activeingredient.

6. The composition of claim 1 in which the active ingredient is 601,11B-difluoro-9-chloro-2l-formyloxy 16a-methyl-1,4-pregnadiene-3,20-dione.

7. The composition of claim 1 in which the active ingredient is 601,11B-difluoro-9-bromo-2l-acetoxy-l6amethyl-1,4-prgnadiene-3 ,20-dione.

8. The composition of claim 1 in which the active in gredient is 601,118-difluoro-9-chloro-21-acetoxy 16amethyl-l ,4-pregnadiene-3 ,20-dione.

9. The composition of claim 1 in which the active ingredient is 6a,1lB-difluoro-9-bromo-2l-hydroxy-16amethyl-1 .4-pregnadiene-3 ,20-dione.

10. The composition of claim 1 in which the active ingredient is 601,11B-difluoro-9-chloro-2 1 -hydroxyl6a-methyl-l ,4-pregnadiene-3,20-dione.

11. The composition of claim 1 in which the active ingredient is601,11B-difluoro-9-bromo-2l-butyryloxy- 16a-methyl-l ,4-pregnadiene-3,20-dione.

12. The composition of claim 1 in which the active ingredient is601,11B-difluoro-9-chloro-2l-butyryloxyloa-methyl-l,4-pregnadiene-3,20-dione.

13..The composition of claim 1 in which the active ingredient is 6a,1lB-difluoro-9-bromo-2 l trimethylacetoxy-l6a-methyl-1,4-pregnadiene-3,20- dione.

14. The composition of claim 1 in which the active ingredient is601,1lB-difluoro-9-chloro-2ltrimethylacetoxy-l6a-methyl-1,4-pregnadiene-3,20-dione.

15. The composition of claim 1 in which the active ingredient is6a-fluoro-9,l1fi-dichloro-21-acetoxy l6a-methyll,4-pregnadiene-3,20-dione.

16. The composition of claim 1 in which the active ingredient is6a-tluoro-l 1B-chloro-9-bromo-21- acetoxy-l 6a-methyl-l ,4-pregnadiene-3,20-dione.

17. The composition of claim 1 in which the active ingredient is6a-fluoro-l 1B-chloro-9-bromo-2lhydroxy-l6a-methyl-1,4-pregnadiene-3,20dione.

18. The composition of claim 1 in which the active ingredient is6a-fluor o-1 1B'-chloro-9-bromo-2lchloroacetoxy-16a-methyl-l,4-pregnadiene-3 ,20- dione.

19. The composition of claim 1 in which the active ingredient is6a-fluoro-9,lIB-dichloro-Zl-hydroxyl6a'methyl-1,4-pregnadiene-3,20-dione.

20. The composition of claim 1 in which the active ingredient isfia-fluoro-l 1B-ch1oro-9-bromo-2 lhexanoyloxy-l6a-methyl-1,4-pregnadiene-3 ,20-dione.

21. The composition of claim 1 in which the active ingredient is6a-fluoro-9,lIB-dichloro-Zl-nitryloxyl6a-methyl-l ,4-pregnadiene-3,20-dione.

22. The composition of claim 1 in which the active ingredient is6a-fluoro-9,l 1 B-dichloro-Z l trimethylacetoxy- 1 fia-methyll,4pregnadiene-3 ,20- dione.

23. The composition of claim 1 in which the active ingredient is 6a,!lB-difluoro-9-chloro-2 1 hexanoyloxy-l Ga-methyl-l ,4-pregnadiene-3,20-dione.

24. The composition of claim 1 in which the active ingredient is6a-fluoro-9,1 lB-dichloro-Z 1- hexanoyloxy-l6a-methyl-l,4-pregnadiene-3,20-dione.

25. The composition of claim 1 in which the active ingredient is6a-fluoro-9,1 lB-dichloro-Z l -butyryloxyl6a-methyl-1 ,4-pregnadiene-3,ZO-dione.

26. The composition of claim 1 in which the active ingredient is6a-fluoro-9,l lfi-dichloro-Zl-valeryloxyloa-methyl-l ,4-pregnadiene-3,20-dione.

27. The composition of claim 1 in which the active ingredient is601,11B-difluoro-9-chloro-2l-valeryloxyl6a-methyl-l ,4-pregnadiene-3,20-dione.

28. The composition of claim 1 in which the active ingredient is6a-fluoro-9a,l lB-dichloro-3,20-dioxol6a-methyl-1 ,4-pregnadiene-2 1-yl-hydrogen succinate.

29. The composition of claim 1 in which the active ingredient issodium-(6a, 1 1B-difluoro-9-chloro-3,20-diox0- l Ga-methyl-l ,4-pregnadiene-21-yl)-sulfate.

30. The composition of claim 1 in which the active ingredient issodium-(6a-fluoro-9,l lB-dichloro-3,20- dioxo-l 6a-methyll,4-pregnadiene-2 1 -yl)-sulfate.

31. The method of treating patients suffering from inflammationscomprising administering to the patient, by injection or by enteral ortopical administration, a pharmaceutical compositions containing aneffective amount of a ll-halogen-steroid as defined in claim 1 and apharmaceutically acceptable carrier therefor.

2. The pharmaceutical composition of claim 1, which is in the form of anointment and contains about 0.0001 to 0.1 percent active ingredient. 3.The pharmaceutical composition of claim 1, which is in the form oftablets, each tablet containing about 0.01 to 50 mg active ingredient.4. The pharmaceutical composition of claim 1, which is in the form ofdrops for eye, nose or ear applications and containing about 0.01 to 1.0percent active ingredient.
 5. The pharmaceutical composition of claim 1,which is in the form of a solution for injection containing about 0.1 to10 percent active ingredient.
 6. The composition of claim 1 in which theactive ingredient is 6 Alpha ,11 Beta -difluoro-9-chloro-21-formyloxy-16Alpha -methyl-1,4-pregnadiene-3,20-dione.
 7. The composition of claim 1in which the active ingredient is 6 Alpha ,11 Beta-difluoro-9-bromo-21-acetoxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 8. The composition of claim 1 inwhich the active ingredient is 6 Alpha ,11 Beta-difluoro-9-chloro-21-acetoxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 9. The composition of claim 1 inwhich the active ingredient is 6 Alpha ,11 Beta-difluoro-9-bromo-21-hydroxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 10. The composition of claim 1 inwhich the active ingredient is 6 Alpha ,11 Beta-difluoro-9-chloro-21-hydroxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 11. The composition of claim 1 inwhich the active ingredient is 6 Alpha ,11 Beta-difluoro-9-bromo-21-butyryloxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 12. The composition of claim 1 inwhich the active ingredient is 6 Alpha ,11 Beta-difluoro-9-chloro-21-butyryloxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 13. The composition of claim 1 inwhich the active ingredient is 6 Alpha ,11 Beta-difluoro-9-bromo-21-trimethylacetoxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 14. The composition of claim 1 inwhich the active ingredient is 6 Alpha ,11 Beta-difluoro-9-chloro-21-trimethylacetoxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 15. The composition of claim 1 inwhich the active ingredient is 6 Alpha -fluoro-9,11 Beta-dichloro-21-acetoxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione. 16.The composition of claim 1 in which the active ingredient is 6 Alpha-fluoro-11 Beta -chloro-9-bromo-21-acetoxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 17. The composition of claim 1 inwhich the active ingredient is 6 Alpha -fluoro-11 Beta-chloro-9-bromo-21-hydroxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.18. The composition of claim 1 in which the active ingredient is 6 Alpha-fluoro-11 Beta -chloro-9-bromo-21-chloroacetoxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 19. The composition of claim 1 inwhich the active ingredient is 6 Alpha -fluoro-9,11 Beta-dichloro-21-hydroxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione. 20.The composition of claim 1 in which the active ingredient is 6 Alpha-fluoro-11 Beta -chloro-9-bromo-21-hexanoyloxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 21. The composition of claim 1 inwhich the active ingredient is 6 Alpha -fluoro-9,11 Beta-dichloro-21-nitryloxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione. 22.The composition of claim 1 in which the active ingredient is 6 Alpha-fluoro-9,11 Beta -dichloro-21-trimethylacetoxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 23. The composition of claim 1 inwhich the active ingredient is 6 Alpha ,11 Beta-difluoro-9-chloro-21-hexanoyloxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 24. The composition of claim 1 inwhich the active ingredient is 6 Alpha -fluoro-9,11 Beta-dichloro-21-hexanoyloxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.25. The composition of claim 1 in which the active ingredient is 6 Alpha-fluoro-9,11 Beta -dichloro-21-butyryloxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 26. The composition of claim 1 inwhich the active ingredient is 6 Alpha -fluoro-9,11 Beta-dichloro-21-valeryloxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione. 27.The composition of claim 1 in which the active ingredient is 6 Alpha ,11Beta -difluoro-9-chloro-21-valeryloxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 28. The composition of claim 1 inwhich the active ingredient is 6 Alpha -fluoro-9 Alpha ,11 Beta-dichloro-3,20-dioxo-16 Alpha -methyl-1,4-pregnadiene-21-yl-hydrogensuccinate.
 29. The composition of claim 1 in which the active ingredientis sodium-(6 Alpha , 11 Beta -difluoro-9-chloro-3,20-dioxo-16 Alpha-methyl-1,4-pregnadiene-21-yl)-sulfate.
 30. The composition of claim 1in which the active ingredient is sodium-(6 Alpha -fluoro-9,11 Beta-dichloro-3,20-dioxo-16 Alpha -methyl-1,4-pregnadiene-21-yl)-sulfate.31. The method of treating patients suffering from inflammationscomprising administering to the patient, by injection or by enteral ortopical administration, a pharmaceutical compositions containing aneffective amount of a 11-halogen-steroid as defined in claim 1.